Immediate disintegration polyvalent polymeric matrix for modified release solid oral preparations and method of preparation thereof

ABSTRACT

An immediate disintegrating polymeric matrix for oral administration with modified release is disclosed, obtained without using inert supports such as sugar spheres, comprising particles of active substance directly covered with a release regulating membrane. Use of such a matrix to prepare various administration forms for oral use as well as the method of its preparation are also disclosed.

FIELD OF THE INVENTION

The present invention relates to an immediate disintegration polymeric polyvalent matrix, suitable for the oral administration of modified release solid products and the related method of its production.

BACKGROUND OF THE INVENTION

The traditional systems to obtain forms of oral administration of medicaments or food supplements with modified release comprise the preparation of tablets, capsules, granulates that once swallowed release the active substance in the gastrointestinal tract according to predeterminated modes.

This release is obtained by application of the active substance on an inert core and then covering the whole with one or more layers of outer membranes comprising substances adapted to provide the desired modified release, that can be a controlled, retarded, extended release according to the substances used for the cover membranes.

In this way the so-called microgranules, pellets or minipellets according to their size are obtained.

However these systems inevitably have some drawbacks, mainly due to the necessity of adding inert ingredients (support cores available on the market, known as sugar spheres) to the active substance. Therefore for the administration of the required dosage, the volume of the final administration form must be increased, with relevant swallowing difficulties, more particularly for high dosages, or the total dosage must be divided into several unitary doses.

SUMMARY OF THE INVENTION

The present invention solves brilliantly and surprisingly the above mentioned problems, with the revolutionary provision of an immediate disintegration polyvalent matrix comprising an agglomerate formed by particles of active substance, directly covered by one or more layers of polymeric membranes having such characteristics as to keep the active substance fully isolated from the outer environment and to adjust the release according to predeterminated modes, thus totally removing the need of an inert support core.

In this way such a matrix can attain an active substance titer much higher than the conventional microgranules, pellets and minipellets, thus allowing to make final administration forms with much higher dosages and better possibility to add other active substances, avoiding to make recourse to divide the total dosage into several unitary doses.

This matrix has a polyvalent function as well, because it allows to make different administration forms of solid oral products, such as high dosage tablets, even fractionable, without altering the modified release characteristics (as it happens with the traditional retard tablets), thus allowing to obtain an optimal flexibility of the unitary dosages to be administered.

These tablets can also be crumbled, in case of swallowing difficulties, in a spoon or directly in the oral cavity and then swallowed with a minimal amount of water or other liquids.

Moreover the matrix in the formulation of disintegrating tablets, to be considered as a mere container or proportioner of the modified release active substance and not as a traditional tablet, allows also to obtain extemporaneous suspensions with a great dosage variety, by disintegrating for instance half tablet=200 mg; one tablet=400 mg; one and a half tablet=600 mg and so forth, in any suitable liquid, and then swallowing the active substance, whose modified release characteristics were not affected, in the form of a homogeneous suspension, very suitable for geriatric and pediatric use.

Moreover the same matrix of the present invention, when used in its simplest form of agglomerate of particles of active substance directly covered with one or more layers of polymeric membrane, allows to make other final dosage forms such as hard gelatine capsules, single dose sachets, oral soluble sachets, bottles with metering stopper.

All the above mentioned forms of dosage cause the active substance to reach promptly after the administration the gastrointestinal tract starting the modified release, at the stomach and/or intestine level according to the properties of the used membrane and in view of the particular characteristics of fine and flowable particle size, the active substance spreads in a quick and uniform way on the whole surface of the gastrointestinal tract.

DETAILED DESCRIPTION OF THE INVENTION

The positive characteristics and advantages of the inventive matrix are numerous and important for the various administration forms that can be formulated and the following may be mentioned without being limited thereto.

Whatever the final implemented form may be, such as tablets, extemporaneous preparations, oral soluble sachets and so on, the matrix always shows the same predeterminated characteristics of progressive, constant and gradual release by diffusion with time.

Even when formulated as a tablet, the matrix always covers a broad surface of the gastrointestinal tract due to the immediate tablet disintegration, with a minimal concentration of the active substance around each particle, with the above mentioned advantages in respect of the traditional tablets, even superior to pellets and minipellets, in view of the finer particle size.

The behavior of the matrix is not affected by the tabletting operation in view of the very reduced particle size and the greater pressure resistance in comparison with the traditional pellets and minipellets as well.

The tablet formulation of the matrix does not cause phenomena of surface polymerisation, that are very frequent with some low melting active ingredients such as thioptic or alpha lipoic acid, a classic problem found with traditional tablets, with consequent release interruption and modification of the retard effect.

Independently from the processed active substance, the matrix components have flavor masking properties, thus allowing the formulation of administration forms having a direct contact with taste buds.

Flavoring or sweetening ingredients may also be added to the matrix components, so that ingestion of these final forms such as fractionable or crumbling tablets, extemporaneous suspensions, single dose sachets and so forth, is also palatable, with clear advantages especially in case of pediatric use.

The components of the matrix have such a specific weight, in view of their minimal size and absence of weighing down inert supports, as to allow a uniform suspension in the liquid used for the extemporaneous suspensions or single dose sachets, for the time required for its ingestion after a minimal shaking of the container, eliminating the product foot remaining in the emptied container, as it frequently happens when administering minipellets.

EXAMPLE

As a merely illustrative and non limiting example of the general application of the present invention, the method of preparation of a polymeric polyvalent matrix of thioptic acid is given hereinafter, a food supplement which is well adapted to be an illustrative example.

To obtain a matrix with the mentioned characteristics it is necessary to have at disposal a starting material with a particle size between 200 and 700 μm.

The method of production to carry out direct application on the active substance of one or more layers of polymeric membrane regulating the release is as follows:

3.0 kg of a starting material having the above stated particle size is charged in a 10 l revolving pan.

While the pan is rotating, the active ingredient is covered using a 30% solution of 300 g shellac in ethanol and 300 g talc.

The covering operation may be effected continuously or in various stages until the required release rate is attained.

At the end of said operation the product is sieved with a 790 μm mesh and dusted with a 425 μm mesh.

The product is left drying in the pan for 3 hours at room temperature.

The finished product has a final titer of 880 mg/g and the release data obtained using the methodology “Dissolution test for solid oral forms” described in the European Pharmacopoeia are the following:

after 1 hour: 18.9%; after 2 hours: 36.0%; after 4 hours: 62.3%; after 8 hours: 86.9%.

The bulk density results to be between 0.3-0.5, so that the product obtained as above stated, can be blended with excipients like cellulose, maize starch, powdered flavors and others, to make a compression obtaining a matrix where the active substance is distributed homogeneously, according to the criteria set by the European Pharmacopoeia.

Matrices produced using a mixture of excipients by direct compression, analysed according to the above described methodology, did not show release variations, so that the method of preparation of the matrices is such as not to cause degradation of lipoic acid and the whole production process keeps the chemical integrity of this active substance.

Finally it is to be pointed out that many variations, additions and/or substitutions may be resorted to the polymeric matrix, more particularly concerning the nature of polymers used as a function of the kind of modified release to be obtained and its method of production, without departing however from its characteristics nor falling out of its scope of protection, as defined in the appended claims. 

1. A prompt disintegration polymeric matrix for oral administration with modified release, comprising particles of active substance directly covered with a release regulating membrane where use of inert supports is eliminated.
 2. The polymeric matrix of claim 1, wherein the cover membrane comprises a solution of shellac in ethanol and talc.
 3. The polymeric matrix of claim 1, wherein the matrix blended with excipients is compressed directly to obtain tablets with immediate disintegration.
 4. The polymeric matrix according to claim 1, wherein the matrix is blended with flavoring and other excipients masking the taste of the active substance, for a better compliance of users.
 5. The polymeric matrix according to claim 1, wherein the active substance is a pharmaceutical substance.
 6. The polymeric matrix according to claim 5, wherein the matrix is a medicament comprising one or more active substances.
 7. The polymeric matrix according to claim 1, wherein the active substance is a food supplement.
 8. The polymeric matrix according to claim 7, wherein the food supplement is thioptic or alpha-lipoic acid.
 9. Use of the matrix according to claim 1, to prepare a homogeneous and uniform extemporaneous suspension in a reduced amount of liquid.
 10. Use of the matrix according claim 1, to prepare hard gelatine capsules.
 11. Use of the matrix according to claim 1, to prepare single dose oral soluble sachets.
 12. A method of preparing a disintegrating polymeric matrix for oral use with modified release according to claim 1, comprising the steps of: charging in a rotary pan a starting material comprising an active substance with particle size between 200 and 700 μm; rotating the pan directly covering the particles of active substance in one or more stages with one or more layers of release regulating polymeric membrane; at the end of the covering step, sieving the product with a mesh of 790 μm and dusting with a mesh of 425 μm; and drying the product in the pan at room temperature.
 13. The method according to claim 12, wherein the polymeric matrix is blended with excipients to make disintegrating tablets and single dose oral soluble sachets.
 14. The method according to claim, wherein the polymeric matrix is blended with flavoring and other excipients for masking the taste of the active substance.
 15. The method according to claim 12, wherein two or more active substances are mixed for a combination therapy or food integration.
 16. The polymeric matrix according to claim 2, wherein the matrix is blended with flavoring and other excipients masking the taste of the active substance, for a better compliance of users.
 17. The polymeric matrix according to claim 3, wherein the matrix is blended with flavoring and other excipients masking the taste of the active substance, for a better compliance of users.
 18. The polymeric matrix according to claim 17, wherein the active substance is a pharmaceutical substance.
 19. The polymeric matrix according to claim 16, wherein the active substance is a pharmaceutical substance.
 20. The polymeric matrix according to claim 15, wherein the active substance is a pharmaceutical substance. 